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Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells.

ABSTRACT: Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

SUBMITTER: Mellini P 

PROVIDER: S-EPMC5915724 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells.

Mellini Paolo P   Marrocco Biagina B   Borovika Diana D   Polletta Lucia L   Carnevale Ilaria I   Saladini Serena S   Stazi Giulia G   Zwergel Clemens C   Trapencieris Peteris P   Ferretti Elisabetta E   Tafani Marco M   Valente Sergio S   Mai Antonello A  

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20180601 1748

Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound <b>1o</b> (<i>N</i>-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1<i>H</i>-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, <b>1o</b> displayed cell growth arrest in breast MDA-MB231, leukaemia K562,  ...[more]

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